IKK phosphorylates IκB, which leads to IκB degradation and allows NF-κB to translocate to the nucleus and activate transcription (Figure 1 ). TNFR-associated factor-2 (TRAF2) and receptor interacting protein (RIP) ( 9) indirectly bind to TNFR1 through TRADD or directly bind to TNFR2 and activate the NF-κB–inducing kinase (NIK) ( 10), which in turn activates the inhibitor of IκB kinase (IKK) complex ( 11-14). The precise functions of IAPs remain to be addressed in the future.Īlthough TNFR mediates apoptotic signal transduction, it can transduce intracellular signals that activate transcription factor nuclear factor κB (NF-κB) by proteolytic breakdown of the inhibitor of κB (IκB). IAPs block caspase-3, caspase-7, and caspase-9 directly, also inhibiting caspase-8 along with TRAFs. The activated NF-κB promotes the transcription of IAPs, as well as proinflammatory cytokines. The NF-κB signal transduction pathway was also initiated through the interaction of TRADD and TRAFs. The activation of caspase-8 or caspase-9 leads to the activation of the caspase cascade. Cytochrome c is released into the cytosol from mitochondria and binds to Apaf1 with adenosine triphosphate (ATP), resulting in the activation of caspase-9. Stimuli other than death receptor activation, such as anticancer drugs, radiation, and reactive oxygen radicals, etc., triggering apoptotic pathways initiate at mitochondria. Recruitment of FADD to Fas or to TNFR through TRADD activates initiator caspase-8. Activation of death receptors resulted in the recruitment of adaptor proteins through interaction of death domain (DD). Death receptor–mediated and mitochondrial-mediated pathways are two principal signaling pathways of apoptosis. Apoptosis signaling pathways mediated by TNFR, Fas, or mitochondria. Furthermore, TNF does not usually kill most type of cells without metabolic inhibitors, which is different from Fas-ligation.įig. Since the Fas-mediated apoptosis-signaling pathway is relatively short and straight compared with that of TNFR, Fas-ligation takes hours to kill target cells, whereas TNF takes a day or more. Another well known death receptor, Fas, also transduces apoptosis signal through FADD and shares the same signaling machinery downstream of FADD with TNFR (Figure 1 ). The death domain is a protein–protein interaction domain, and adopter molecules FADD and TRADD use these domains to interact with other death domain– containing molecules and trigger the apoptosis-signaling pathway. Death domain is the sequence in TNFR1, TRADD, and FADD. TRADD interacts with Fas-associated death domain protein (FADD) ( 8) to activate caspase-8, thereby initiating the apoptosis pathway. Most cytotoxic effects of TNF are mediated by TNFR1 through interaction of its death domain with the TNFR-associated death domain protein (TRADD) ( 7). The cellular effects of TNF are mediated by two distinct cell surface receptors termed TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) ( 6). TNF causes inflammation by damaging tissues and by inducing the expression of adhesion molecules and cytokines in epithelial and endothelial cells, as well as in inflammatory cells. Tumor necrosis factor (TNF)-α is a proinflammatory cytokine, which can induce a broad spectrum of biologic effects and is associated with inflammatory lung disease. Therefore, epithelial cell injury is the common manifestation of lung injury, and apoptosis contributes to such injury of epithelial cells. DNA damage and apoptosis in lung epithelial cells have been reported in acute lung injury ( 3), diffuse alveolar damage ( 4), and idiopathic pulmonary fibrosis (IPF) ( 5). An intratracheal injection of agonistic anti-Fas antibody into adult mice causes epithelial cell apo-ptosis and lung inflammation, which subsequently leads to pulmonary fibrosis ( 2). Second, excessive apoptosis may cause disease. Repair after an acute lung injury requires the elimination of proliferating mesenchymal and inflammatory cells from the alveolar air space or alveolar wall ( 1). First, failure to clear unwanted cells by apoptosis will prolong the inflammation because of the release of their toxic contents. Apoptosis may also play important roles in lung diseases in two different ways. Dysregulation of apoptosis may be involved in human diseases such as cancer, AIDS, degenerative and autoimmune diseases, and infectious diseases. Apoptosis has been implicated as a physiologic cell death program critical for homeostasis.
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